Silybin is a flavone compound extracted from seed coats of seeds of a compositae medicinal plant, i.e. silybum marianum. The flavone compound is poor in water solubility and lipid solubility. The structural formula is as follows:

Silybin has an obvious hepatoprotective effect, has different levels of protection and treatment effects on various types of hepatic injury caused by hepatic poisons such as carbon tetrachloride, thioacetamide, hydroxycholine, phalloidine, mucronatine, etc., and has a certain inhibition effect on increasing of alanine aminotransferase caused by carbon tetrachloride. As an ideal hepatic injury repairing medicine, silybin is widely and clinically used for treating hepatopathy such as acute and chronic hepatitis, hepatic fibrosis, early hepatocirrhosis, etc. Due to high medicine effects and low toxicity (Yu Yuecheng, Gu Changhai. Research Progress in Pharmacologic Effect of Silymarin [J]. Chinese Journal of Hospital Pharmacy, 2001, 21(8): 493-494.), silybin has received great attention from discovery.
At present, the preparations sold in China comprise silybin meglumine tablets (approval number: H32026233 approved by the state; manufacturer: Jiangsu Zhongxing Pharmaceutical Co., Ltd.; approval number: H33022182 approved by the state; manufacturer: Zhejiang Donzri Pharmaceutical Co., Ltd.) and silybin capsules (commodity name: Shui Lin Jia; approval number: H20040299 approved by the state; manufacturer: Tianjin Tasly Pharmaceutical Co., Ltd.). The preparations are all oral preparations. The silybin is poor in water solubility and lipid solubility (Wang Hongchen. Research on Dissolving Property of Silymarin [J]. Chinese Pharmaceutical Bulletin, 1983, 19(12): 23-25.), resulting in low oral bioavailability and relatively high first-pass effect. According to report, the absolute bioavailability of silybin taken orally is only 0.95% (Wu J W, et al. Analysis of silybin in rat plasma and bile for hepatobiliary excretion and oral bioavailability application [J]. J Pharm Biomed Anal, 2007, 45(4): 635-641.), and therefore, the exertion of medicine effects of the silybin oral preparations is severely weakened. Thus, people are intended to further exert the medicine effects by improving the bioavailability of silybin. The broad masses of medicinal workers are intended to improve the dissolution of silybin using techniques such as salification, solubilization, solid dispersion, etc. so as to improve the oral absorptivity, but the high effect is not achieved. In addition, Tianjin Tasly Pharmaceutical Co., Ltd. developed a silybin-phosphatidylcholine complex (common name: silybin capsules; commodity name: Shui Lin Jia; approval number: H20040299 approved by the state); and the silybin-phosphatidylcholine complex has been sold in the market. Researches indicate that the dissolution and the bioavailability of the silybin-phosphatidylcholine complex are obviously improved in comparison with those of the common silybin oral preparations and the bioavailability is improved by 3-5 times (Filburn C R, et al. Bioavailability of silybin-phosphatidylcholine complex in dogs [J]. J Vet Pharmccol Ther, 2007, 30(2): 132-138, silybin-phosphatidylcholine complex [M]. Altern Med Rev, ID: Thorne Research, Inc. 2009, 14(4): 385-390.), but the bioavailability is still not ideal. Thus, people consider developing silybin into an injection so as to fundamentally solve the problem of low oral bioavailability.
Song Yunmei et al. (Song Yunmei et al. Preparation of Silybin Nanoemulsion and Pharmacokinetics in Rabbits [J] Journal of China Pharmaceutical University, 2005, 36(5): 427.) developed a silybin nanoemulsion. Since the solubility of silybin is poor, and a large amount of cremophor RH is added into a formulation, the material has severe anaphylaxis and hemolysis, and the safety is poorer. In addition, since silybin is soluble in water under an alkaline condition, researchers developed a silybin N-methylglucamine injection, but silybin is very unstable in an alkaline environment, so that the injection has relatively poor long-term storage stability and is easy to degrade. Therefore, someone prepared a silybin meglumine solution into a freeze-dried powder injection. Although the problem of placement stability of the silybin meglumine solution can be solved, the pH value of the silybin N-methylglucamine aqueous solution is about 11, and thus, the local irritation is high and more adverse effects are generated during injection. According to clinical application of silybin in recent years, it is verified that silybin has precise curative effect and very low toxicity, and the clinical application of silybin is extremely wide. If a safe and injectable silybin preparation can be developed, the bioavailability can be improved, and the pharmacological effect can be fully exerted, so that the medicine effect can be greatly improved, and the great economic and social benefits can be necessarily generated.
A cyclodextrin inclusion compound is formed by wrapping medicine molecules in cavity structures of cyclodextrin molecules, thereby solving the dissolution problem of water-insoluble medicines. However, it is known that the conventional cyclodextrin materials have obvious hemolysis or renal toxicity, such as β-cyclodextrin, hydroxypropyl-β-cyclodextrin, etc. The Chinese patent application CN200410041364.0 with the title “preparation method of cyclodextrin inclusion compound of silybin marianum extract and medicinal preparation thereof” and the publication number. of CN159351A has the key technical features of dissolving silybin extract with cyclodextrin using ethanol or isopropanol, performing reduced-pressure evaporation to remove ethanol or isopropanol, and then adding some excipients to prepare an oral preparation or directly sub-packaging to form a sterile powder for injection. The types of cyclodextrin recorded in the Claims and Description are as follows: β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, methyl-β-cyclodextrin, glucosyl-β-cyclodextrin and sulfonyl-β-cyclodextrin. These types of cyclodextrin are conventional cyclodextrin having large toxic and adverse effects, and cannot be truly applied to preparations for intravenous injection, and therefore, the whole embodiment is oriented to the oral preparation and the matching property of the cyclodextrin is not further researched. It is verified through tests that all the types of cyclodextrin defined in this patent cannot be prepared into stable silybin injections (See embodiment 1 of the present invention). The Chinese patent application CN02125823.6 with the title “silymarin injection containing cyclodextrin or derivatives thereof” and the publication number of CN1391894A, according to the implementing scheme recorded in the Description, has the key technical features of adding silymarin into an aqueous solution containing cyclodextrin, regulating the pH of the solution to alkalinity using sodium hydroxide to dissolve silybin, and then regulating the pH value to be 6.0 to 6.5 using hydrochloric acid to obtain a silymarin cyclodextrin inclusion compound, wherein the types of the cyclodextrin are exactly same as that of the patent application (Chinese patent application CN200410041364.0). It is verified through tests that in the process of dissolving silybin in an alkaline aqueous solution of sodium hydroxide, the color of the solution turns dark gradually, and the solution is finally changed into a yellow green solution; through full-wavelength scanning, a greater absorption peak occurs in the part of 326.0 nm again besides the great adsorption occurs in the original part of 287.5 nm, thereby indicating that sodium hydroxide has the effect of obviously breaking the structure of silymarin; and therefore, the quality of the silymarin cyclodextrin inclusion compound prepared by the patent application has a certain problem and may influence the safety and effectiveness. Meanwhile, the freeze-dried powder injection prepared according to the implementing scheme fails to re-dissolve fully after freeze-drying (See embodiment 33 of the present invention). In addition, the types of cyclodextrin recorded in the Claims and Description are conventional cyclodextrin having large toxic and adverse effects, and have potential safety hazard such as hemolysis or renal toxicity.
Sulfobutylether-β-cyclodextrin (SBE-β-CD) is an ionized β-cyclodextrin (β-CD) developed by Cydex Pharmaceuticals, Inc., and has the advantages of good water solubility, no renal toxicity and no hemolysis in comparison with the conventional cyclodextrin materials. Therefore, in combination with the physicochemical properties of silybin, the present invention firstly utilizes sulfobutylether-β-cyclodextrin (SBE-β-CD) to solve the dissolution problem of silybin. Through a great quantity of test researches, a silybin sulfobutylether-β-cyclodextrin inclusion compound is successfully developed and is a safe and stable silybin injection, thereby overcoming the defect of low oral bioavailability of silybin fundamentally, and providing a novel preparation for the clinical research and application.